Composition for making gastro-resistant gelatin capsules

ABSTRACT

The invention provides a new gelatine composition suitable for producing capsules having better resistance to enzymes, better mechanical strength, improved resistance to moisture and a longer storage life than known capsules. This composition essentially comprises the combination product of gelatine, water, glycerine and/or sorbitol and a silicone fluid having an intrinsic viscosity of from 100 to 12,500.

United States Patent Rolle [4 1 Apr. 4, 1972 COMPOSITION FOR MAKINGGASTRO- [56] References Cited RESISTANT GELATIN CAPSULESUNITEDSTATESPATENTS [72] Bemheim 3,489,567 1/1970 McGraw 106/125 [73]Assignee: R. P. Scherr Corporation 2,899,327 8/1959 Christopher 106/ l36 [22] Filed: Dec. 23, 1969 Primary Examiner-Theodore Moms [2]] Appl'887787 Attorney-Karl W. Flocks [30] Foreign Application Priority Data[57] ABSTRACT Dec. 27, 1968 France ..l81 144 Th i ti provides a newgelatine composition suitable for producing capsules having betterresistance to enzymes, [52] US. Cl ..106/125, 106/126, 424/37, bettermechanical Strength improved resistance to'moismre 424/360 and a longerstorage life than known capsules. This composi- [51] Int. Cl. ..C09d3/04 u h d f 58 Field of Search ..106/l25, 126 essema Y e ma gelatine,water, glycerine and/or sorbitol and a silicone fluid having anintrinsic viscosity of from 100 to 12,500.

2 Claims, No Drawings COMPOSITION FOR MAKING GASTRO-RESISTANT GELATINCAPSULES The present invention relates to improved gelatine capsules.

The pharmaceutical industry currently uses capsules and gelloids made ofgelatine. Whatever their composition may be, these gelloids and capsulesdo not always have a high resistance to enzymes, good mechanicalstrength, and a high resistance to moisture; and their storage life isfrequently limited. In addition, gelatine capsules and gelloids whichare resistant to gastric fluids, and are produced by subjecting them toa particular treatment which will be referred to later, have a certainnumber of drawbacks.

Thus, for example, it is desirable to have available resistant gelatinecapsules which are entero-soluble, in order that certain activeconstituents which have a bad smell or a bad taste, or are veryvolatile, are not liberated or do not function until they have passedthe stomach. Gastro-resistant capsules are also advantageous either forthe administration of active substances which are unstable in the acidmedium of the stomach or for the administration of delayed actionpreparations, or for the administration of preparations which may havean irritant action on the mucous membranes of the stomach.

It is already known to prepare gastro-resistant gelatine capsules bytreating the gelatine envelope with rapid-action aldehydes,oxy-aldehydes, di-ketones or oxy-ketones, and especially withformaldehydes.

Nevertheless, the known methods for the manufacture of gastro-resistantgelatine capsules had the disadvantage of requiring a longstorage-period of the capsules, (of the order or several weeks), beforethe optimum effect was obtained, since the action of the treating agentis slow and gradual, and stability is only reached after a considerabletime.

Furthermore, with known capsule compositions, it is relatively difficultto make sure that the fixed quantity of the treating agent is the samefrom one batch of capsules to another, or even from one capsule toanother.

A main object of the present invention is to provide a new gelatinecomposition suitable for producing capsules having a better resistanceto enzymes, better mechanical strength, improved resistance to moistureand a longer storage life than known capsules.

Another object of the invention is to provide gelatine capsules capableof being readily converted to gastro-resistant capsules which haveproperties and characteristics superior to those of knowngastro-resistant capsules.

A further object of the invention is to provide gelatine capsules whichare particularly suitable for treatment with aldehydes, and especiallywith formaldehyde, in order to impart improved gastro-resistantproperties.

According to the invention, there is provided a composition for themanufacture of gastro-resistant capsules and gelloids of gelatine,comprising the combination of gelatine, water, glycerine and/orsorbitol, and a silicone fluid having an intrinsic viscosity between land 12,500. i

The invention also provides improved gelatin capsules produced from theabove defined composition and rendered gastro-resistant by treatmentwith an aldehyde.

According to other feature of the invention, the basic composition ofthe capsules comprises, in the combined state, from l to 90 percent ofsilicone fluid with respect to the total weight of gelatine plus waterplus glycerine and/or sorbitol.

The silicone fluid is advantageously selected from dimethylpolysiloxanesand methylphenyl-polysiloxanes having an intrinsic viscosity between 100and 12,500.

Capsules according to the invention are produced by mixing togetherwater, gelatine, glycerine and/or sorbitol and silicone fluid in thefollowing ranges of proportions water Glycerine and/or sorbitol GelatineI Silicone Gelatine from 20% to 50% (by weight) Glycerine and/orsorbitol 0.5% (by weight) Water from 50% to (by weight) Silicone from 1%to 50% (by weight) with respect to the total weight of the gelatine,glycerine and/or sorbitol and water.

This operation is carried out in a conventional mixer which can beheated under vacuum, and the whole mass is heated up to completemelting. From this molten. mass, the capsules are made in any mannerknown per se.

The aldehyde agent for the subsequent treatment of the capsules thusproduced is preferably formaldehyde.

This treatment can be effected by immersion, by spraying, or preferablyby sprinkling the capsules.

The aldehyde agent is advantageously dispersed in a very volatile,water-miscible solvent.

The volatile water-miscible solvent is advantageously acetone. 1:150.

The concentration of the aldehyde treatment solution preferablycorresponds to a ratio of 30 percent formaldehyde solution to acetone of1:50 to 1:150.

Other characteristic features and advantages of the invention will bebrought out more clearly from the following description.

The present invention provides capsules having improved characteristicsas compared with known types of gelatine capsules, in particularresistance to enzymes, mechanical strength, resistance to moisture and along storage life. The invention provides also capsules having the abovecharacteristics but also capable of being converted to gastro-resistantcapsules having improved characteristics as compared with knowncapsules.

The Applicant has discovered that when gelatine, water, glycerine orsorbitol, or a combination of glycerine and sorbitol, and a siliconefluid with or without other conventional additives used in thecomposition of gelatine capsules (such as coloring agents andplastifying agents) are combined in the molten state, there is obtaineda mass which, by fabrication by a conventional process, gives capsuleshaving the characteristics referred to above. The Applicant has alsodiscovered that when these capsules are subsequently treated (afterstorage or immediately after their manufacture) with formaldehyde indispersion in a volatile water-miscible solvent, there are obtainedgastro-resistant capsules which do not have the disadvantages of knowngastro-resistant capsules and which exhibit entirely unexpectedcharacteristics namely, that the optimum effect of gastro-resistance isobtained at the end of 4 days, and that the time of opening of a capsulein gastric juices is constant and independent of the storage time.

Tests carried out with artificial gastric juices have in fact shown thatthe gastro-resistance in vitro of capsules stored for a very long timeand of capsules having been stored for only 96 hours is, constant at aminimum of 2 hours. The time of opening in the intestinal juices alsoremains remarkably con stant, irrespective of the period of storage.

These facts are surprising and although at the present time notheoretical explanation has been found, it may be assumed that thesilicones selectively block certain functions of the gelatine molecule,so that the possible subsequent reaction process with the formaldehydeis different from that which has been obtained hitherto, in the sensethat the formaldehyde only reacts with the functional groups which arenot blocked.

This being the case, in view of the particular behaviour of the basicgelatine capsules according to the invention, it thus becomes possibleto regulate in a simple and accurate manner the gastro-resistance andthe time of opening of the capsules in the intestinal juices, byregulating the large amount of formaldehyde used.

Tests carried out on the basic capsules according to the invention haveproved that the thickness of the envelope of the capsules had no effecton the period of opening of the capsules treated with aldehyde. This hasled to the discovery that in order to calculate the theoretical quantityof aldehyde necessary for the treatment it is no longer necessary, as inthe prior art, to refer to the weight of the capsules but rather totheir surface area independently of their geometric shape.

During the production of the gelatine mass for the preparation ofcapsules according to the invention, it is possible, without anydisadvantage, to use conventional additives such as plasticisers,coloring agents, opacifiers, fillers and preserving agents (such aspotassium sorbate).

in the production of the capsules according to the invention, there isadded to the glycerine and/or sorbitol and water, from 1 to 90 percentof fluid silicone or a mixture of silicone fluids, which are mixedtogether with gelatine and added to the mixture. The operation iscarried out in a conventional mixer which can be heated, for example amixer of stainless steel or similar material, and under vacuum. Thewhole mixture is heated until the mass is totally melted. To this massthere may be added colouring agents, or plasticisers or other additives.From this mixture, capsules are then made by any method known per se,and these may be stored. They have very good characteristics ofresistance to enzymes, mechanical strength and resistance to moisture,and they may be stored for very long periods without any sign ofdegradation or decomposition.

The capsules thus prepared may, immediately after their manufacture orafter any period of storage, be treated with a solution of aldehyde,preferably formaldehyde, in dispersion in a highly volatilewater-miscible solvent, preferably acetone. This treatment may becarried out by immersion or by spraying, but preferably by sprinklingthe capsules.

In practice, especially when the sprinkling method is adopted, use isadvantageously made of a dispersion (in the case of treatment of asurface area of 1,000 sq. cm. of cap sules) comprising about 266 mg. ofsolution of formaldehyde at 30 percent strength, corresponding to 79.8mg. of formaldehyde. The ratio of 30 percent formaldehyde to acetone is1:60.

The formaldehyde content of the solution is checked at the beginning ofthe operation and from time to time during the course of operation. Forthis check, use is made of the BOU- GAULT and GROS method (oxidationwith iodine and titration on return of the excess iodine).

It should however be specified that, depending on the process selectedfor applying the aldehyde and according to the period of contact of thislatter with the capsules, and depending on the degree ofgastro-resistance and the required time of opening in the intestinaljuices, use may be made of other concentrations of the formaldehydedispersion.

The application of formaldehyde to the capsules can be effected in anyappropriate manner, but, in order to avoid washing the treated capsulesand their subsequent drying, and thus to ensure an optimum rapid action,this application is effected in the following manner:

In a turbine used for making pills, there are provided on the internalface of this turbine, driving, guiding and acceleration devices for therotation of the capsules by means of strips arranged in staggeredrelation, and the capsules thus driven are sprinkled by the admission ofthe treatment solution by means of nozzles or sprinkling roses openinginto the chamber of the turbine.

This process ensures a complete wetting of the capsules by thedispersion of formaldehyde, and the acetone evaporates so rapidly, thevapours being evacuated by a suction device, that it is possible to packthe capsules immediately after treatment without any drying by hot air,for example, being necessary.

One example of capsule-making according to the invention is set outbelow by way of example.

EXAMPLE 22.020 kg. of glycerine and 34.130 kg. of water are mixed with10 kg. of dimethyl-polysiloxane or methyl-phenyl-polysiloxane (of 1,000intrinsic viscosity) and 43.850 kg. of gelatine are added. This mixtureis melted under vacuum in a tank of stainless steel, with agitation, ata temperature between 75 and C. until the melting is absolutelycomplete.

The opaque mass thus obtained is then used for making the capsules inthe usual manner. These capsules are resistant to enzymes and have animproved mechanical strength and resistance to moisture. Their period ofstorage without any degradation is practically unlimited.

Capsules of this kind can be employed for the preparation ofgastro-resistant capsules by proceeding in the following manner:

15,000 capsules are introduced into a turbine used for making pills oflarge size, the inner face of which is lined with guiding andaccelerating strips for rotating the capsules and by means of a tubecommunicating with a tank of a formaldehyde-dispersion in acetone in theratio of 1:60 (formaldehyde at 30 percent strength in acetone); thesecapsules are sprinkled by using 755 grams of this dispersion.

The formaldehyde is immediately and integrally fixed by the gelatinewhile the acetone is instantaneously evacuated by a suction deviceprovided on the said turbine.

The capsules thus treated can be immediately packed, and the wholeoperation of treatment, including packing, requires about 10 minutes.

The gastro-resistance in vitro and the time of opening in the intestinaljuices at 37 C. were measured, using capsules treated by theconventional method (A) and capsules treated according to the invention(B), this measurement being made as a function of the ageing of thecapsules.

The results have shown that in the case of the new capsules (B) thegastro-resistance of 2 hours was reached 4 days after treatment, whilein the case of the known capsules (A), this gastro-resistance was onlyobtained 6 weeks after the treatment, the time of opening in theintestinal juices in the case of (B) for an ageing period of 2 months toone year being practically constant at 200 seconds.

For these measurements, the method USP XVll, (pages 919 to 921) wasused. This method consists in subjecting the capsules for 1 hour to theaction of artificial gastric juices and then to the action of artificialintestinal juices, and in measuring the time of opening in the saidartificial intestinal juices.

1n the case of the known capsules (A) and for the same ageing times,this time of opening varies from 300 to 620 seconds.

I claim:

1. A composition for the manufacture of gastro-resistant gelatinecapsules, consisting essentially of the combination of from 23 to 27percent by weight of water, from 17 to 29.5 percent by weight of acompound selected from glycerine and sorbitol, from 58 to 33.5 percentby weight of gelatine, and of from 1 to percent with respect to water,gelatine and said selected compound, of a silicone fluid selected fromdimethylpolysiloxanes and methyl-phenyl-polysiloxanes having anintrinsic viscosity between and 12,500.

2. A composition for the manufacture of gastro-resistant gelatinegelloids consisting essentially of the combination of from 50 to 80percent by weight of water, 0.5 percent by weight of a compound selectedfrom gylcerine and sorbitol, from 20 to 50 percent by weight ofgelatine, and of from 1 to 50 percent with respect to water, gelatineand said selected compound, of a silicone fluid selected fromdimethylpolysiloxanes and methyl-phenyl-polysiloxanes having anintrinsic viscosity between 100 and 12,500.

UNITED STATES PATENT OFFICE CERTIFICATE OF CQRRECT'ION' Patent NO.3,653,934 Dated April 4, 1972 Invent r( FERNAND JACQUES ROLLE It iscertified that error appears in the above-identified patent and thatsaid Letters Patent are hereby corrected as shown below:

In column 1, line 4, the name of the ass ignee should read: R. P.Scherer Corporation inn-zed and sealed this 8th day of August 1972.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. ROBERT GUTTSCHALK Attesting Officer Commissionerof Patents FORM POQIOSO (10439) USCQMM-DC 60376-P69 1" u 5 GOVERNMENTPRINTING OFFICE: I959 0-356-334

2. A composition for the manufacture of gastro-resistant gelatine gelloids consisting essentially of the combination of from 50 to 80 percent by weight of water, 0.5 percent by weight of a compound selected from gylcerine and sorbitol, from 20 to 50 percent by weight of gelatine, and of from 1 to 50 percent with respect to water, gelatine and said selected compound, of a silicone fluid selected from dimethyl-polysiloxanes and methyl-phenyl-polysiloxanes having an intrinsic viscosity between 100 and 12,500. 